Phenyl-thiazolyl inhibitors of pro-matrix metalloproteinase activation

Abstract

This invention relates to phenyl thiazole I and its therapeutic and prophylactic uses, wherein the variables R z , Q, J, R 1 , R 3 , R 5 , R 6 , and R 7 are defined in the specification. Disorders treated and/or prevented include rheumatoid arthritis.

1 . The compounds of Formula I 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is C (1-4) alkoxy, C (1-4) alkyl, SC (1-4) alkyl, Cl, F, OCH 2 C (3-6) cycloalkyl, OC (3-6) cycloalkyl, OCH 2 CF 3 , SCH 2 C (3-6) cycloalkyl, SC (3-6) cycloalkyl, SCF 3 , or OCF 3 ; 
         Q is N or C—R 2 ; 
         R 2  is H, or CH 3 ; or R 2  and R 1  may be taken together with the ring to which they are attached, to form a fused ring system selected from the group consisting of: quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, napthalyl, benzofuranyl, 2,3-dihydro-benzofuranyl, benzothiophenyl, benzothiazolyl, benzotriazolyl, indolyl, indolinyl, and indazolyl, wherein said quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, benzothiazolyl, napthalyl, benzofuranyl, 2,3-dihydro-benzofuranyl, benzothiophenyl, benzotriazolyl, indolyl, indolinyl, and indazolyl are optionally substituted with one methyl group or up to two fluorine atoms; 
         R 3  is Cl, SO 2 NH 2 , SO 2 CH 3 , CO 2 H, CONH 2 , NO 2 , —CN, CH 3 , CF 3 , or H; 
         J is N, or C—R 4 ; 
         R 4  is F, NH 2 , NHC (1-3) alkyl, N(C (1-3) alkyl) 2 , C (1-3) alkyl, —CN, —CH═CH 2 , —CONH 2 , —CO 2 H, —NO 2 , —CONHC (1-4) alkyl, CON(C (1-4) alkyl) 2 , C (1-4) alkylCONH 2 , —NHCOC (1-4) alkyl, —CO 2 C (1-4) alkyl, CF 3 , SO 2 C (1-4) alkyl, —SO 2 NH 2 , —SO 2 NH(C (1-4) alkyl), —SO 2 N(C (1-4) alkyl) 2 , —CONHC (2-4) alkyl-piperidinyl, —CONHC (2-4) alkyl-pyrrolidinyl, —CONHC (2-4) alkyl-piperazinyl, —CONHC (2-4) alkyl-morpholinyl, —CONHCH 2 Ph, or R 4  is selected from the group consisting of: phenyl, pyridyl, pyrimidyl, pyrazyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, and thiophenyl wherein said phenyl, pyridyl, pyrimidyl, pyrazyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, and thiophenyl are optionally substituted with one R d ; provided that R 4  may be H, if R 3  is SO 2 NH 2 , SO 2 CH 3 , CO 2 H, or CONH 2 ; or R 3  and R 4  may both be H, provided that the ring to which they are attached is pyridyl; or R 4  may also be H provided that R 1  and R 2  are taken together with the ring to which they are attached, to form a fused ring system; or R 4  and R 3  may be taken together with the ring to which they are attached, to form the fused ring system 2,3-dihydroisoindolin-1-one; 
         R d  is C (1-4) alkyl, F, Cl, Br, —CN, or OC (1-4) alkyl; 
         R 5  is H, F, Cl, Br, CF 3 , or CH 3 ; 
         R 6  is H, C (1-3) alkyl, OCH 3 , F, Cl, Br, —CN, or CF 3 ; or if R 7  is H, C (1-3) alkyl, OCH 3 , F, Cl, Br, —CN, or CF 3 , then R 6  is 
       
       
         
           
           
               
               
           
         
         SO 2  C (1-4) alkylNA 1 A 2 , SOC (1-4) alkylNA 1 A 2 , pyridinyl, pyrimidinyl, pyrazinyl, NA 1 A 2 , C(O)NA 1 A 2 , SO 2 NA 1 A 2 , SONA 1 A 2 , C(O)N(C (1-3) alkyl)C (2-6) alkylNA 1 A 2 , C(O)NHC (2-6) alkylNA 1 A 2 , NHC(O)C (1-6) alkylNA 1 A 2 , N(C (1-3) alkyl)C(O)C (1-6) alkylNA 1 A 2 , C (1-6) alkylOC (2-6) alkylNA 1 A 2 , C (1-6) alkylNHC (2-6) alkylNA 1 A 2 , C (1-6) alkylN(C (1-3) alkyl)C (2-6) alkylNA 1 A 2 , NHC (2-6) alkylNA 1 A 2 , N(C (1-3) alkyl)C (2-6) alkylNA 1 A 2 , OC (2-6)  alkylNA 1 A 2 , or C (1-6) alkylNA 1 A 2 ; 
         wherein any piperidinyl in R 6  may be optionally substituted with up to four methyl groups on two or more ring carbon atoms or optionally substituted with up to two CF 3  groups on any two ring carbon atoms; 
         A 1  is H, or C (1-3) alkyl; 
         A 2  is H, C (1-6) alkyl, CH 2 C (3-6) cycloalkyl, C (1-6) cycloalkyl, 
       
       
         
           
           
               
               
           
         
       
       C (2-6) alkylOH, C (2-6) alkylOCH 3 , C (2-6) alkylCO 2 C (1-4) alkyl, SO 2 C (1-4) alkyl, C(O)Ph, C(O)C (1-4) alkyl, pyrazinyl, or pyridyl, wherein said cycloalkyl, alkyl, pyrazinyl, pyridyl, or Ph groups may be optionally be substituted with two substituents selected from the group consisting of F, C (1-6) alkyl, CF 3 , pyrrolidinyl, CO 2 H, C(O)NH 2 , SO 2 NH 2 , OC (1-4) alkyl, —CN, NO 2 , OH, NH 2 , NHC (1-4) alkyl, N(C (1-4) alkyl) 2 ; and said pyridyl, or Ph may be additionally be substituted with up to two halogens independently selected from the group consisting of: Cl, and Br; or A 1  and A 2  are taken together with their attached nitrogen to form a ring selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein any said A 1  and A 2  ring, except imidazolyl, may be optionally substituted with up to four methyl groups on two or more ring carbon atoms or optionally substituted with up to two CF 3  groups on any two ring carbon atoms, or optionally substituted with one —CONH 2  group on any one ring carbon atom; 
         R k  is selected from the group consisting of H, CO 2 C(CH 3 ) 3 , CH 2 CF 3 , CH 2 CH 2 CF 3 , C (1-6) alkyl, COC (1-4) alkyl, SO 2 C (1-4) alkyl, trifluoromethylpyridyl, CH 2 C (3-6) cycloalkyl, CH 2 -phenyl, and C (3-6) cycloalkyl; 
         R m  is H, OCH 3 , CH 2 OH, NH(C (1-4) alkyl), N(C (1-4) alkyl) 2 , NH 2 , C (1-6) alkyl, F, or OH; and 
         R 7  is H, C (1-3) alkyl, OCH 3 , F, Cl, Br, —CN, or CF 3 ; or if R 6  is H, C (1-3) alkyl, OCH 3 , F, Cl, Br, —CN, or CF 3  then R 7    
         is 
       
       
         
           
           
               
               
           
         
       
       SO 2 C (1-4) alkylNA 1 A 2 , SOC (1-4) alkylNA 1 A 2 , pyridinyl, pyrimidinyl, pyrazinyl, NA 1 A 2 , C(O)NA 1 A 2 , SO 2 NA 1 A 2 , SONA 1 A 2 , C(O)N(C (1-3) alkyl)C (2-6) alkylNA 1 A 2 , C(O)NHC (2-6) alkylNA 1 A 2 , NHC(O)C (1-6) alkylNA 1 A 2 , N(C (1-3) alkyl)C(O)C (1-6) alkylNA 1 A 2 , C (1-6) alkylOC (2-6) alkylNA 1 A 2 , C (1-6) alkylNHC (2-6) alkylNA 1 A 2 , C (1-6) alkylN(C (1-3) alkyl)C (2-6) alkylNA 1 A 2 , NHC (2-6) alkylNA 1 A 2 , N(C (1-3) alkyl)C (2-6) alkylNA 1 A 2 , OC (2-6) alkylNA 1 A 2 , or C (1-6) alkylNA 1 A 2 ;
 wherein any piperidinyl in R 7  may be optionally substituted with up to four methyl groups on two or more ring carbon atoms or optionally substituted with up to two CF 3  groups on any two ring carbon atoms; 
 and 
 R z  is independently selected from the group consisting of H, C (1-3) alkyl, OCH 3 , F, Cl, Br, —CN, and CF 3 ; 
 and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. 
 
     
     
         2 . A compound of  claim 1 , wherein:
 R 2  is H, or CH 3 ; or R 2  and R 1  may be taken together with the ring to which they are attached, to form a fused ring system selected from the group consisting of: quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, benzofuranyl, 2,3-dihydro-benzofuranyl, benzothiophenyl, benzothiazolyl, and indazolyl, wherein said quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, benzothiazolyl, benzofuranyl, 2,3-dihydro-benzofuranyl, benzothiophenyl, and indazolyl are optionally substituted with one methyl group or up to two fluorine atoms;   R 4  is F, CH 3 , —CN, —CONH 2 , —CO 2 H, —NO 2 , —CONHC (1-4) alkyl, C (1-4) alkylCONH 2 , —NHCOC (1-4) alkyl, —CO 2 C (1-4) alkyl, CF 3 , SO 2 C (1-4) alkyl, —SO 2 NH 2 , —SO 2 NH(C (1-4) alkyl), or R 4  is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, and thiophenyl wherein said pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, and thiophenyl are optionally substituted with one R d ; provided that R 4  may be H, if R 3  is SO 2 NH 2 , SO 2 CH 3 , CO 2 H, or CONH 2 ; or R 3  and R 4  may both be H, provided that the ring to which they are attached is pyridyl; or R 4  may also be H provided that R 1  and R 2  are taken together with the ring to which they are attached, to form a fused ring system;   R d  is CH 3 , F, Cl, Br, —CN, or OCH 3 ;   R 6  is   
       
         
           
           
               
               
           
         
         NA 1 A 2 , C(O)NA 1 A 2 , SO 2 NA 1 A 2 , SONA 1 A 2 , C(O)N(CH 3 )C (2-6) alkylNA 1 A 2 , C(O)NHC (2-6) alkylNA 1 A 2 , NHC(O)C (1-6) alkylNA 1 A 2 , N(CH 3 )C(O)C (1-6) alkylNA 1 A 2 , CH 2 OC (2-6) alkylNA 1 A 2 , CH 2 NHC (2-6) alkylNA 1 A 2 , CH 2 N(CH 3 )C (2-6) alkylNA 1 A 2 , NHC (2-6) alkylNA 1 A 2 , N(CH 3 )C (2-6) alkylNA 1 A 2 , OC (2-6) alkylNA 1 A 2 , or CH 2 NA 1 A 2 ; 
         A 1  is H, or C (1-3) alkyl; 
         A 2  is H, C (1-6) alkyl, CH 2 C (3-6) cycloalkyl, C (1-6) cycloalkyl, 
       
       
         
           
           
               
               
           
         
         C (2-6) alkylOH, C (2-6) alkylOCH 3 , C (2-6) alkylCO 2 C (1-3) alkyl, SO 2 C (1-4) alkyl, C(O)Ph, C(O)C (1-4) alkyl, pyrazinyl, or pyridyl; 
         or A 1  and A 2  are taken together with their attached nitrogen to form a ring selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein any said A 1  and A 2  ring, except imidazolyl, may be optionally substituted with up to four methyl groups on two or more ring carbon atoms or optionally substituted with up to two CF 3  groups on any two ring carbon atoms, or optionally substituted with one —CONH 2  group on any one ring carbon atom; 
         R k  is selected from the group consisting of H, CO 2 C(CH 3 ) 3 , CH 2 CF 3 , CH 2 CH 2 CF 3 , C (1-5) alkyl, COC (1-4) alkyl, SO 2 C (1-4) alkyl, CH 2 C (3-6) cycloalkyl, CH 2 -phenyl, and C (3-6) cycloalkyl; 
         R m  is H, OCH 3 , CH 2 OH, NH(C (1-4) alkyl), N(C (1-4) alkyl) 2 , NH 2 , CH 3 , F, or OH; 
         R 7  is H, C (1-3) alkyl, OCH 3 , F, Cl, Br, —CN, or CF 3 ; and 
         R z  is independently selected from the group consisting of H, and CH 3 ; 
         and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. 
       
     
     
         3 . A compound of  claim 2 , wherein:
 R 2  is H, or CH 3 ; or R 2  and R 1  may be taken together with the ring to which they are attached, to form a fused ring system selected from the group consisting of: quinolinyl, benzofuranyl, and 2,3-dihydro-benzofuranyl, wherein said quinolinyl, benzofuranyl, and 2,3-dihydro-benzofuranyl are optionally substituted with one methyl group or up to two fluorine atoms;   R 4  is F, —CN, —CONH 2 , —CO 2 H, —NO 2 , —CO 2 C (1-4) alkyl, SO 2 C (1-3) alkyl, —SO 2 NH 2 , CH 2 CONH 2 , or R 4  is selected from the group consisting of: pyrazolyl, and oxazolyl, wherein said pyrazolyl, and oxazolyl are optionally substituted with one R d ; provided that R 4  may be H, if R 3  is SO 2 NH 2 , SO 2 CH 3 , CO 2 H, or CONH 2 ; or R 3  and R 4  may both be H, provided that the ring to which they are attached is pyridyl; or R 4  may also be H provided that R 1  and R 2  are taken together with the ring to which they are attached, to form a fused ring system;   R d  is CH 3 , F, or Cl;   R 5  is H, F, Cl, Br, or CH 3 ;   R 6  is   
       
         
           
           
               
               
           
         
         NA 1 A 2 , C(O)NA 1 A 2 , SO 2 NA 1 A 2 , SONA 1 A 2 , C(O)N(CH 3 )C (2-3) alkylNA 1 A 2 , C(O)NHC (2-3) alkylNA 1 A 2 , NHC(O)C (1-3) alkylNA 1 A 2 , N(CH 3 )C(O)C (1-3) alkylNA 1 A 2 , CH 2 OC (2-3) alkylNA 1 A 2 , CH 2 NHC (2-3) alkylNA 1 A 2 , CH 2 N(CH 3 )C (2-3) alkylNA 1 A 2 , NHC (2-3) alkylNA 1 A 2 , N(CH 3 )C (2-3) alkylNA 1 A 2 , OC (2-3) alkylNA 1 A 2 , or CH 2 NA 1 A 2 ; 
         A 1  is H, or C (1-3) alkyl; 
         A 2  is H, C (1-5) alkyl, CH 2 -cyclopropyl, C (2-6) alkylOCH 3 , CH 2 CH 2 CO 2 CH 2 CH 3 , C (2-6) alkylOH, 
       
       
         
           
           
               
               
           
         
         C(O)C (1-4) alkyl; 
         or A 1  and A 2  are taken together with their attached nitrogen to form a ring selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R k  is selected from the group consisting of H, CO 2 C(CH 3 ) 3 , C (1-3) alkyl, COC (1-4) alkyl, SO 2 C (1-4) alkyl, CH 2 CH 2 CF 3 , CH 2 CF 3 , CH 2 -cyclopropyl, CH 2 -phenyl, and C (3-6) cycloalkyl; 
         R m  is H, OCH 3 , CH 2 OH, NH(CH 3 ), N(CH 3 ) 2 , NH 2 , CH 3 , F, or OH; 
         R 7  is H, CH 3 , F, Cl, or Br; and 
         and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. 
       
     
     
         4 . A compound of  claim 3 , wherein:
 R 1  is OC (1-4) alkyl, SC (1-4) alkyl, C (1-4) alkyl, OCH 2 C (3-5) cycloalkyl, OC (3-5) cycloalkyl, or OCF 3 ;   R 2  is H; or R 1  and R 2  may be taken together with their attached ring to form 2,3-dihydrobenzofuran-7-yl, or 2-methyl benzofuran-7-yl;   R 3  is SO 2 NH 2 , SO 2 CH 3 , CO 2 H, CONH 2 , CH 3 , —CN, or H;   R 4  is F, —CN, —CONH 2 , —CO 2 H, SO 2 C (1-3) alkyl, —SO 2 NH 2 , —NO 2 , CH 2 CONH 2 , or R 4  is selected from the group consisting of: pyrazolyl, and oxazolyl, wherein said pyrazolyl, and oxazolyl are optionally substituted with one R d ; provided that R 4  may be H, if R 3  is SO 2 NH 2 , SO 2 CH 3 , CO 2 H, or CONH 2 ; or R 3  and R 4  may both be H, provided that the ring to which they are attached is pyridyl; or R 4  may also be H provided that R 1  and R 2  are taken together with the ring to which they are attached, to form a fused ring system;   R 5  is H;   R 6  is   
       
         
           
           
               
               
           
         
         NA 1 A 2 , C(O)NA 1 A 2 , SO 2 NA 1 A 2 , SONA 1 A 2 , C(O)N(CH 3 )C (2-3) alkylNA 1 A 2 , C(O)NHC (2-3) alkylNA 1 A 2 , NHC(O)C (1-3) alkylNA 1 A 2 , N(CH 3 )C(O)C (1-3) alkylNA 1 A 2 , CH 2 OC (2-3) alkylNA 1 A 2 , CH 2 NHC (2-3) alkylNA 1 A 2 , CH 2 N(CH 3 )C (2-3) alkylNA 1 A 2 , NHC (2-3) alkylNA 1 A 2 , N(CH 3 )C (2-3) alkylNA 1 A 2 , OC (2-3) alkylNA 1 A 2 , or CH 2 NA 1 A 2 ; 
         A 1  is H, or C (1-3) alkyl; 
         A 2  is H, C (1-5) alkyl, CH 2 -cyclopropyl, C (2-3) alkylOCH 3 , CH 2 CH 2 CO 2 CH 2 CH 3 , CH 2 CH 2 OH, 
       
       
         
           
           
               
               
           
         
         C(O)C (1-4) alkyl; 
         or A 1  and A 2  are taken together with their attached nitrogen to form a ring selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R k  is selected from the group consisting of H, CO 2 C(CH 3 ) 3 , C (1-3) alkyl, COC (1-4) alkyl, SO 2 C (1-4) alkyl, CH 2 CH 2 CF 3 , CH 2 CF 3 , CH 2 -cyclopropyl, CH 2 -phenyl, and C (3-6) cycloalkyl; 
         R m  is H, OCH 3 , CH 2 OH, NH(CH 3 ), N(CH 3 ) 2 , NH 2 , CH 3 , F, or OH; 
         and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. 
       
     
     
         5 . A compound of  claim 4 , wherein:
 R 1  is OC (1-3) alkyl, isobutyl, or OCF 3 ;   Q is C—R 2 ;   R 3  is H, or CH 3 ;   R 4  is F, CONH 2 , or SO 2 NH 2 ;   R 6  is OC (2-3) alkylNA 1 A 2 , CH 2 NA 1 A 2 , NA 1 A 2 ,   
       
         
           
           
               
               
           
         
         A 1  and A 2  are taken together with their attached nitrogen to form a ring selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         R k  is H, cyclopropyl, C (1-3) alkyl, or CH 2 -phenyl; and 
         R 7  is H, or Br; and 
         R z  is H; 
         and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. 
       
     
     
         6 . A compound of  claim 1 , wherein:
 R 1  is OCH(CH 3 ) 2 ;   Q is C—R 2 ;   R 2  is H;   R 3  is H;   J is C—R 4 ;   R 4  is F, —CONH 2 , —CO 2 H, or —SO 2 NH 2 ;   R 5  is H;   and solvates, hydrates, tautomers, and pharmaceutically available salts thereof.   
     
     
         7 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and solvates, hydrates, tautomers, and pharmaceutically acceptable salts thereof. 
     
     
         8 . A pharmaceutical composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         9 . A pharmaceutical composition comprising a compound listed in the Examples section of this specification and a pharmaceutically acceptable carrier. 
     
     
         10 . A method for preventing, treating or ameliorating an MMP9 mediated syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of  claim 1  or a form, composition or medicament thereof. 
     
     
         11 . A method for preventing, treating or ameliorating an MMP9 mediated syndrome, disorder or disease wherein said syndrome, disorder or disease is associated with elevated MMP9 expression or MMP9 overexpression, or is a condition that accompanies syndromes, disorders or diseases associated with elevated MMP9 expression or MMP9 overexpression comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof. 
     
     
         12 . A method of preventing, treating or ameliorating a syndrome, disorder or disease, wherein said syndrome, disorder or disease is selected from the group consisting of: neoplastic disorders, osteoarthritis, rheumatoid arthritis, cardiovascular diseases, gastric ulcer, pulmonary hypertension, chronic obstructive pulmonary disease, inflammatory bowel syndrome, periodontal disease, skin ulcers, liver fibrosis, emphysema, Marfan syndrome, stroke, multiple sclerosis, asthma, abdominal aortic aneurysm, coronary artery disease, idiopathic pulmonary fibrosis, renal fibrosis, and migraine, comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof. 
     
     
         13 . The method of  claim 12 , wherein said syndrome, disorder or disease is a neoplastic disorder, which is ovarian cancer. 
     
     
         14 . The method of  claim 12 , wherein said syndrome, disorder or disease is a cardiovascular disease, wherein said cardiovascular disease is selected from the group consisting of: atherosclerotic plaque rupture, aneurysm, vascular tissue morphogenesis, coronary artery disease, and myocardial tissue morphogenesis. 
     
     
         15 . The method of  claim 14 , wherein said cardiovascular disease is atherosclerotic plaque rupture. 
     
     
         16 . The method of  claim 12 , wherein said syndrome, disorder or disease is rheumatoid arthritis. 
     
     
         17 . The method of  claim 12 , wherein said syndrome, disorder or disease is asthma. 
     
     
         18 . The method of  claim 12 , wherein said syndrome, disorder or disease is chronic obstructive pulmonary disease. 
     
     
         19 . The method of  claim 12 , wherein said syndrome, disorder or disease is inflammatory bowel syndrome. 
     
     
         20 . The method of  claim 12 , wherein said syndrome, disorder or disease is abdominal aortic aneurism. 
     
     
         21 . The method of  claim 12 , wherein said syndrome, disorder or disease is osteoarthritis. 
     
     
         22 . The method of  claim 12 , wherein said syndrome, disorder or disease is idiopathic pulmonary fibrosis. 
     
     
         23 . A method of inhibiting MMP9 activity in a mammal by administration of an effective amount of at least one compound of  claim 1 . 
     
     
         24 . A method for preventing, treating or ameliorating an MMP13 mediated syndrome, disorder or disease comprising administering to a subject in need thereof an effective amount of a compound of  claim 1  or a form, composition or medicament thereof. 
     
     
         25 . A method for preventing, treating or ameliorating an MMP13 mediated syndrome, disorder or disease wherein said syndrome, disorder or disease is associated with elevated MMP13 expression or MMP13 overexpression, or is a condition that accompanies syndromes, disorders or diseases associated with elevated MMP13 expression or MMP13 overexpression comprising administering to a subject in need thereof an effective amount of a compound of Formula I or a form, composition or medicament thereof. 
     
     
         26 . A method of inhibiting MMP13 activity in a mammal by administration of an effective amount of at least one compound of  claim 1 .